Substituted chroman derivatives

ABSTRACT

The present invention relates to new piperidyl- or piperazinyl-substituted dihydro-2H-1-benzopyran derivatives having the formula (I)  
                 
wherein X is N; 
     Y is NR 2 CH 2 , CH 2 NR 2 , NR 2 CO, CONR 2 , NR 2 SO 2  or NR 2 CONR 2  
       wherein R 2  is H or C 1 -C 6  alkyl;    
       R 1  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl;    R 3  is C 1 -C 6  alkyl, C 3 -C 6  cycoalkyl or (CH 2 ) n -aryl, 
       wherein aryl is a heteromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R 4  and/or R 5 ; and n is 0-4; as (R)-enantiomers, (S)-enantiomers or racemates in the form of a free base or a pharmaceutically acceptable salt or solvate thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds.

This application is a divisional of U.S. application Ser. No.10/714,577, filed Nov. 13, 2003, which is a divisional of U.S.application Ser. No. 10/285,743, filed Nov. 1, 2002, now U.S. Pat. No.6,670,359, which is a divisional of U.S. application Ser. No.09/171,570, filed Oct. 21, 1998, now U.S. Pat. No. 6,479,497, which wasthe National Stage of International Application No. PCT/SE98/01603,filed Sep. 9, 1998.

FIELD OF THE INVENTION

The present invention relates to new piperidyl- orpiperazinyl-substituted dihydro-2H-1-benzopyran derivatives as(R)-enantiomers, (S)-enantiomers or racemates in the form of free baseor pharmaceutically acceptable salts or solvates thereof, a process fortheir preparation, pharmaceutical compositions containing saidtherapeutically active compounds and to the use of said active compoundsin therapy.

An object of the invention is to provide compounds for therapeutic use,especially compounds having a selective effect at a subgroup of5-hydroxytryptamine receptors, designated the h5-HT_(1B)-receptor(previously called the 5-HT_(1Dβ)-receptor) in mammals including man.

It is also an object of the invention to provide compounds with atherapeutic effect after oral administration.

BACKGROUND OF THE INVENTION

Various central nervous system disorders such as depression, anxiety,etc. appear to involve the disturbance of the neurotransmittersnoradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also knownas serotonin. The drugs most frequently used in the treatment ofdepression are believed to act by improving the neurotransmission ofeither or both of these physiological agonists. It appears that theenhancement of 5-HT neurotransmission primarily affects the depressedmood and anxiety, whereas the enhancement of noradrenalineneurotransmission affects the retardation symptoms occurring indepressed patients. The invention concerns compounds which have aneffect on 5-HT neurotransmission.

Serotonin, or 5-HT, activity is believed to be involved in manydifferent types of psychiatric disorders. For instance it is believedthat an increase in 5-HT activity is associated with anxiety, while adecrease in 5-HT release has been associated with depression. Serotoninhas in addition been implicated in such diverse conditions as eatingdisorders, gastrointestinal disorders, cardiovascular regulationdisorders and sexual disturbances.

The 5-HT Receptors

The various effects of 5-HT may be related to the fact thatserotoninergic neurons stimulate the secretion of several hormones, e.g.cortisol, prolactin, β-endorphin, vasopressin and others. The secretionof each of these other hormones appears to be regulated on a specificbasis by several different 5-HT (serotonin) receptor subtypes. With theaid of molecular biology techniques, to date these receptors have beenclassified as 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆ and 5-HT₇ withthe 5-HT₁ receptor further divided into the 5-HT_(1A), 5-HT_(1B),5-HT_(1D), 5-HT_(1E) and 5-HT_(1F) subtypes. Each receptor subtype isinvolved in a different serotonin function and has different properties.

Regulation of the 5-HT Transmission

The release of 5-HT is feedback-regulated by two different subtypes of5-HT receptors. Inhibitory 5-HT_(1A) autoreceptors are located on thecell bodies in the raphé nuclei which upon stimulation by 5-HT decreasethe impulse propagation in the 5-HT neurons and thereby reduce the 5-HTreleased at the nerve terminals. Another subtype of inhibitory 5-HTreceptors is located on the 5-HT nerve terminals, the h5-HT_(1B)receptors (in rodents the r5-HT_(1B) receptors) which regulate thesynaptic concentration of 5-HT by controlling the amount of 5-HT that isreleased. An antagonist of these terminal autoreceptors thus increasesthe amount of 5-HT released by nerve impulses which has been shown inboth in vitro and in vivo experiments.

The use of an antagonist of the terminal h5-HT_(1B) autoreceptor willaccordingly increase the synaptic 5-HT concentration and enhance thetransmission in the 5-HT system. It would thus produce an antidepressanteffect making it useful as a medication for depression.

Other localizations of h5-HT_(1B) receptor subtype also exist. A largepart of these postsynaptic receptors appear to be located on nerveterminals of other neuronal systems (so called heteroreceptors). Sincethe h5-HT_(1B) receptor mediates inhibitory responses an antagonist ofthis receptor subtype might also increase the release of otherneurotransmitters than 5-HT. Compounds having h5-HT_(1B) activity mayaccording to well known and recognised pharmacological tests be dividedinto full agonists, partial agonists and antagonists.

Disclosure of the Invention

The object of the present invention is to provide compounds having aselective effect at the h5-HT_(1B) receptor, preferably antagonisticproperties, as well as having a good bioavailability. The effect on theother receptors chosen from, for example, the 5-HT_(1A), 5-HT_(2A), D₁,D_(2A), D₃, α₁ and α₂ receptor has been investigated.

Accordingly, the present invention provides compounds of the formula I

wherein

-   X is N or CH;-   Y is NR₂CH₂, CH₂—NR₂, NR₂—CO, CO—NR₂, NR₂SO₂ or NR₂CONR₂    -   wherein R₂ is H or C₁-C₆ alkyl;-   R₁ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;-   R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl,    wherein aryl is phenyl or a heteroaromatic ring containing one or    two heteroatoms selected from N, O and S and which may be mono- or    di-substituted with R₄ and/or R₅;    -   wherein R₄ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halogen, CN,        CF₃, OH, C₁-C₆ alkoxy, NR₆R₇, OCF₃, SO₃CH₃, SO₃CF₃, SO₂NR₆R₇,        phenyl, phenyl-C₁-C₆ alkyl, phenoxy, C₁-C₆ alkylphenyl, an        optionally substituted heterocyclic ring containing one or two        heteroatoms selected from N, O, S, SO and SO₂ wherein the        substituent(s) is(are) selected from C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl-C₁-C₆ alkyl, (CH₂)_(m)OR₉ wherein m is 2-6        and R₉ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl-C₁-C₆        alkyl, and COR₈, an optionally substituted heteroaromatic ring        containing one or two heteroatoms selected from N, O and S        wherein the substituent(s) is(are) selected from C₁-C₆ alkyl,        C₃-C₆ cycloalkyl and phenyl-C₁-C₆ alkyl, or COR₈;        -   wherein R₆ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;        -   R₇ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and        -   R₈ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, CF₃, NR₆R₇, phenyl, a            heteroaromatic ring containing one or two heteroatoms            selected from N, O and S or a heterocyclic ring containing            one or two heteroatoms selected from N, O, S, SO and SO₂;    -   R₅ is H, OH, CF₃, OCF₃, halogen, C₁-C₆ alkyl or C₁-C₆ alkoxy;    -   and n is 0-4;        as (R)-enantiomers, (S)-enantiomers or a racemate in the form of        a free base or a pharmaceutically acceptable salt or solvate        thereof which possess a high selective effect at the h5-HT_(1B)        receptor and also show sufficient bioavailability after oral        administration.

In the present context C₁-C₆ alkyl may be straight or branched. C₁-C₆alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl ori-hexyl.

In the present context C₁-C₆ alkoxy may be straight or branched. C₁-C₆alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy, n-hexyloxy or i-hexyloxy.

In the present context C₃-C₆ cycloalkyl may be cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, preferably cyclohexyl.

In the present context halogen may be fluoro, chloro, bromo or iodo.

In the present context the heteroaromatic ring containing one or twoheteroatoms selected from N, O and S preferably is a 5- or 6-memberedheteroaromatic ring and may be furyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring canbe either substituted or unsubstituted.

In the present context the heterocyclic ring containing one or twoheteroatoms selected from N, O, S, SO and SO₂ may optionally contain acarbonyl function and is preferably a 5-, 6- or 7-membered heterocyclicring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino,1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.

A preferred embodiment of the invention relates to compounds of formulaI wherein Y is NHCO or CONH i.e. amides. Of these compounds, thecompounds wherein R₃ is unsubstituted phenyl, or mono- or di-substitutedphenyl, and especially ortho-, meta- or para-substituted phenyl, andparticularly these wherein the substituent R₄ is phenyl, phenyl-C₁-C₆alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF₃,4-piperidon-1-yl, n-butoxy or COR₈ wherein R₈ is phenyl, cyclohexyl,4-piperidon-1-yl, 1-piperazinyl, morpholino, CF₃, piperidino or NR₆R₇,are preferred.

Examples of Combinations of Substituents are:

-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is hydroxyethyl-piperazinyl, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl;-   X is N, Y is NR₂ CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is morpholino,-   R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is morpholino, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is morpholino, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is hydroxyethyl-piperazinyl, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is benzyloxyethyl-piperazinyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)-phenyl;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is morpholino, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is benzyloxyethyl-piperazinyl, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is COR₈, R₈ is morpholino;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is piperidino, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is COR₈,-   R₈ is NR₆R₇, R₆R₇CH₃, C₂H₅ or C₃H₇;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is morpholino, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is COR₈, R₈ is morpholino;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperazinyl, R₅ is H;-   X is CH, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is piperidino,-   R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl, R₄ is phenyl, phenylmethyl or phenylethyl, R₅ is H;-   X is CH, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is piperidino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    (CH₂)₂-phenyl, R₄ is morpholino, R₅ is H;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is piperazinyl, R₅ is H;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl, R₄ is COR₈, R₈ is cyclohexyl;-   X is N, Y is CONR₂, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    phenyl;-   X is N, Y is NR₂CO, R₁ is H, CH₃, C₂H₅ or C₃H₇, R₂ is H, R₃ is    CH₂-phenyl.

Preferred compounds are:

-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]4-morpholinobenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]4-piperidinobenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-butoxybenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-N,N-diethylaminobenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(4-piperidon-1-yl)benzamide-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(hexahydro-1,4-diazepin-5-on-1-yl)benzamide,    and-   (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4    dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide.

The compounds of the present invention are in the form of the racemateor the (R)- or (S)-enantiomer in the form of a free base or apharmaceutically acceptable salt or solvate thereof. Compounds in theform of the (S)-enantiomer are preferred ones.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic,hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric,dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic,sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic,phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic,3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic,naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic andbenzoic acids. These salts are readily prepared by methods known in theart.

The preferred solvates of the compounds of this invention are thehydrates.

Pharmaceutical Formulations

In a second aspect the present invention provides a pharmaceuticalformulation comprising as active ingredient a therapeutically effectiveamount of the compound of formula I as an enantiomer or a racemate inthe form of a free base or a pharmaceutically acceptable salt or solvatethereof, optionally in association with diluents, excipients or inertcarriers.

According to the present invention the compound of the invention willnormally be administered orally, rectally or by injection, in the formof pharmaceutical formulations comprising the active ingredient eitheras a free base or a pharmaceutically acceptable non-toxic acid additionsalt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate,sulfate, sulfamate, citrate, tartrate, oxalate and the like in apharmaceutically acceptable dosage form. The dosage form may be a solid,semisolid or liquid preparation. Usually the active substance willconstitute between 0.1 and 99% by weight of the preparation, morespecifically between 0.5 and 20% by weight for preparations intended forinjection and between 0.2 and 50% by weight for preparations suitablefor oral administration.

To produce pharmaceutical formulations containing the compound of theinvention in the form of dosage units for oral application, the selectedcompound may be mixed with a solid excipient, e.g. lactose, saccharose,sorbitol, mannitol, starches such as potato starch, corn starch oramylopectin, cellulose derivatives, a binder such as gelatine orpoly-vinylpyrrolidone, and a lubricant such as magnesium stearate,calcium stearate, polyethylene glycol, waxes, paraffin, and the like,and then compressed into tablets. If coated tablets are required, thecores, prepared as described above, may be coated with a concentratedsugar solution which may contain, e.g. gum arabic, gelatine, talcum,titanium dioxide, and the like. Alternatively, the tablet can be coatedwith a polymer known to the person skilled in the art, dissolved in areadily volatile organic solvent or mixture of organic solvents.Dyestuffs may be added to these coatings in order to readily distinguishbetween tablets containing different active substances or differentamounts of the active compound.

For the preparation of soft gelatine capsules, the active substance maybe admixed with e.g. a vegetable oil or poly-ethylene giycol. Hardgelatine capsules may contain granules of the active substance usingeither the above mentioned excipients for tablets, e.g. lactose,saccharose, sorbitol, mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine. Also liquidsor semisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstance in a mixture with a neutral fatty base, or gelatine rectalcapsules comprising the active substance in admixture with vegetable oilor paraffin oil. Liquid preparations for oral application may be in theform of syrups or suspensions, for example solutions containing fromabout 0. 1% to about 20% by weight of the active substance hereindescribed, the balance being sugar and a mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharin andcarboxymethyl-cellulose as a thickening agent or other excipients knownto the person skilled in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance, preferably in a concentration of from about 0.1%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

Suitable daily doses of the compound of the invention in therapeuticaltreatment of humans are about 0.01-100 mg/kg bodyweight at peroraladministration and 0.001-100 mg/kg bodyweight at parenteraladministration.

The compound of the invention may be used in a combination with a 5-HTreuptake inhibitor, such as fluoxetine, paroxetine, citalopram,clomipramine, sertraline, alaproclate or fluvoxamin, preferablyparoxetine or citalopram. Another possible combination is to use thecompound of the invention together with a monoamine oxidase inhibitor,such as moclobemide, tranylcypramine, brofaromide or phenelzine,preferably moclobemide or phenelzine. Still another possible combinationis the compound of the invention together with a 5-HT_(1A) antagonist,such as the compounds disclosed in WO 96/33710, preferably(R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran.

Medical and Pharmaceutical Use

In a further aspect the present invention provides the use of thecompounds of formula I in therapy as a h5-HT_(1B) antagonist, partialagonist or full agonist, preferably as an antagonist and the use in thetreatment of 5-hydroxytryptamine mediated disorders. Examples of suchdisorders are disorders in the CNS such as mood disorders (depression,major depressive episodes, dysthymia, seasonal affective disorder,depressive phases of bipolar disorder), anxiety disorders (obsessivecompulsive disorder, panic disorder with/without agoraphobia, socialphobia, specific phobia, generalized anxiety disorder, posttraumaticstress disorder), personality disorders (disorders of impulse control,trichotellomania), obesity, anorexia, bulimia, premenstrual syndrome,sexual disturbances, alcoholism, tobacco abuse, autism, attentiondeficit, hyperactivity disorder, migraine, memory disorders (ageassociated memory impairment, presenile and senile dementia),pathological aggression, schizophrenia, endocrine disorders (e.g.hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease,thermoregulation, pain and hypertension. Other examples ofhydroxytryptamine mediated disorders are urinary incontinence, vasospasmand growth control of tumors (e.g. lung carcinoma).

Methods of Preparation

The present invention also relates to processes for preparing thecompound of formula I. Throughout the following description of suchprocesses it is understood that, where appropriate, suitable protectinggroups will be added to, and subsequently removed from, the variousreactants and intermediates in a manner that will be readily understoodby one skilled in the art of organic synthesis. Conventional proceduresfor using such protecting groups as well as examples of suitableprotecting groups are described, for example, in “Protective Groups inOrganic Synthesis” T. W. Greene, Wiley-Interscience, New York, 1991.

Methods of Preparation of Intermediates

1. In the Case where Y is NR₂CO and X is N

-   (i) Benzylation of the compound of the formula II, described in:    Thorberg S-O.; Hall H.; Åkesson C.; Svensson K.; Nilsson J. L. G.    Acta Pharm. Suec. 1987, 24(4), 169-182 as a racemate or in the    patent application WO 93/07135 as an enantiomer,    to obtain a compound of formula III may be carried out by reaction    with a suitable benzylation agent, e.g. a benzyl halide such as    benzyl bromide or benzyl chloride or an activated alcohol, e.g.    benzyl mesylate or benzyl tosylate. The reaction may be carried out    using a salt or the base of compound II in a suitable solvent, e.g.    N,N-dimethylformamide, acetone or acetonitrile, with a suitable    base, e.g. NaOH, NaHCO₃, K₂CO₃ or a trialkylamine such as    triethylamine, at a temperature within the range of +20° C. to    +150° C. The presence of a suitable catalyst, e.g. potassium iodide    or sodium iodide, may increase the speed of the reaction.-   (ii) Demethylation of the compound of formula III    to obtain a compound of formula IV may be carried out by treating    the compound with an acidic reagent such as aqueous HBr, HI,    HBr/CH₃COOH, BBr₃, AlC1₃, pyridine-HCl or with a basic nucleophilic    reagent such as CH₃C₆H₄S⁻ or C₂H₅S⁻ in a suitable solvent. Suitable    solvents may be methylene chloride or chloroform and the reaction    may occur between −78° C. and +60° C.-   (iii) Conversion of the compound of formula IV to a compound of    formula V    may be carried out by the reaction with a compound of formula VI    where Lg denotes for a leaving group, e.g. a halogen such as    chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group    such as a p-toluenesulfonyloxy group and R_(a) and R_(b) are    hydrogen or a lower alkyl group, e.g. methyl. The process may be    carried out with a salt of the compound of formula IV obtained by    reaction with a base such as K₂CO₃, Na₂CO₃, KOH, NaOH, BuLi or NaH.    The reaction may be conducted in a suitable solvent, e.g. an aprotic    solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran,    toluene, benzene or petroleum ether and the reaction may occur    between +20° C. and +150° C.-   (iv) Rearrangement of a compound of formula V to a compound of    formula VII    may be carried out in a suitable solvent, e.g. aprotic solvent such    as N,N dirnethylformamide, dioxane, 1,1,3,3-tetramethylurea,    tetrahydrofuran or hexamethylphosphoric triamide, with a suitable    base, e.g. K₂CO₃, KOH, potassium tert-butoxide or NaH, at a    temperature within the range of +20° C. to +150° C. The presence of    a cosolvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone    or hexamethyl-phosphoric triamide in appropriate concentration in    the solvent may increase the speed of the reaction.-   (v) Hydrolysis of a compound of formula VII to a compound VIII may    be carried out under acidic conditions using acids such as H₂SO₄,    HCl or HBr in a suitable solvent, e.g. H₂O, ethanol, methanol or    mixtures thereof, and the reaction may occur between +20° C. and    +100° C. or under basic conditions using bases such as NaOH or KOH    in a suitable solvent, e.g. H₂O, ethanol, methanol or mixtures    thereof, and the reaction may occur between +20° C. and +100° C.-   (vi) Conversion of compound of formula VIII to a compound of formula    IX    may be carried out by-   a) reaction with a compound of formula X    where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl. The process may be    carried out in a suitable solvent, e.g. an aprotic/anhydrous solvent    such as tetrahydrofuran or N,N-dimethylformamide, in the presence of    a coupling reagent such as N,N′-carbonyldiimidazole and the reaction    may occur between +20° C. and +130° C. The reaction is followed by    the reduction of the imide with a suitable reducing agent, e.g.    LiAlH₄, in a suitable solvent, e.g. diethyl ether or tetrahydrofuran    at a temperature between +20° C. and reflux, or-   b) by reaction with a compound of formula XI    where Lg denotes a leaving group, e.g. a halogen such as chlorine,    bromine or iodine or an alkane- or arenesulfonyloxy group such as    p-toluenesulfonyloxy group and R₁ is hydrogen, C₁-C₆-alkyl or C₃-C₆    cycloalkyl. The process may be carried out in a suitable solvent    such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a    mixture of water and acetonitrile with a suitable base, e.g. K₂CO₃,    NaHCO₃ or KOH, and the reaction may occur between +20° C. and +150°    C.-   (vii) Conversion of the compound of formula IX to a compound of    formula XII    where R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl may be carried out by-   a) hydrogenation using a catalyst containing palladium, platinum,    rhodium or nickel in a suitable solvent, e.g. acetic acid or    ethanol, and at a reaction temperature between +20° C. and +120° C.,    or-   b) debenzylation in a suitable solvent such as methanol in the    presence of ammonium formate and Pd/C and at a reaction temperature    between +20° C. and reflux.-   (viii) Conversion of a compound of formula IX, where R₁ is hydrogen,    to a compound of formula XIII,    where R_(c) denotes a suitable protecting group, may be carried out    by-   a) hydrogenation using a catalyst containing palladium, platinum,    rhodium or nickel in a suitable solvent, e.g. acetic acid or    ethanol, at a reaction temperature between +20° C. and +120° C., or-   b) debenzylation in a suitable solvent such as methanol in the    presence of ammonium formate and Pd/C at a reaction temperature    between +20° C. and reflux.

Said reaction is followed by the protection of the piperazine ring in asuitable solvent, e.g. methylene chloride or chloroform, with anappropriate protecting reagent e.g. di-tert-butyl dicarbonate with asuitable base, e.g. triethylamine or K₂CO₃, and at a temperature between−20° C. and +60° C., resulting in compound of formula XIII.

2. In the Case where Y is NR₂CO and X is CH

-   (i) Halogenation of the compound of formula XIV, either as a    racemate (described in: Thorberg S-O.; Hall H.; Åkesson C.; Svensson    K.; Nilsson J. L. G. Acta Pharm. Suec. 1987, 24(4), 169-182), or as    an enantiomer    to obtain a compound of formula XV may be performed by aromatic    electrophilic substitution using a suitable halogenation agent such    as Br₂, Cl₂, I₂, ICl, or SO₂Cl₂. The reaction may be carried out    using the salt or the base of the compound XIV in an appropriate    solvent, e.g. acetic acid, HCI/ethanol or water, with or without a    suitable base, e.g. an alkali metal acetate such as sodium acetate    and at a reaction temperature between −20° C. and room temperature.-   (ii) Benzylation of the compound of the formula XV, either as a    racemate or as an enantiomer, to obtain a compound of the formula    XVI may be carried out by reaction with a suitable benzylation    agent, e.g. benzyl halide such as benzyl bromide or benzyl chloride.    The reaction may be carried out using the salt or the base of    compound XV in a suitable solvent, e.g. N,N-dimethylformamide,    acetone or acetonitrile, with a suitable base such as triethylamine,    NaOH, NaHCO₃ or K₂CO₃ at a temperature within the range of +20° C.    to +150° C. The presence of a suitable catalyst, e.g. an alkali    metal halide such as potassium iodide or sodium iodide, may increase    the speed of the reaction.-   (iii) The conversion of the compound of the formula XVI to the    compound of the formula XVII, where R₁ is C₁-C₆ alkyl or C₃-C₆    cycloalkyl, may be performed by a metal-halogen exchange, in an    appropriate anhydrous solvent such as tetrahydrofuran or diethyl    ether using a suitable alkyllithium or metal, e.g. butyllithium,    lithium or magnesium turnings, followed by treatment with an    appropriate piperidone such as N-methyl-4-piperidone and a    subsequent suitable workup. The reaction may be performed at a    reaction temperature within the range of −78° C. to room    temperature.-   (iv) The compound of the formula XVII may be reduced to the compound    of the formula XVIII by treatment with a suitable reducing agent    such as sodium borohydride and a protonating agent such as CF₃COOH,    CF₃SO₃H or HCOOH in an appropriate solvent such as tetrahydrofuran    or diethyl ether. The reaction may be performed at a reaction    temperature between 0° C. and reflux.-   (v) Demethylation of the compound of the formula XVIII to obtain a    compound of formula XIX may be performed by treating the compound    with an acidic reagent such as aqueous HBr, HI, HBr/acetic acid,    BBr₃, AlCl₃, pyridine-HCl or with a basic nucleophilic reagent such    as C₂H₅S⁻ or CH₃CH₄S⁻ in a suitable solvent. Suitable solvents may    be methylene chloride or chloroform and the reaction may occur    between −78° C. and +60° C.-   (vi) Conversion of the compound of formula XIX to a compound of    formula XX may be carried out with a compound such as    trifluoromethanesulfonic anhydride in a suitable solvent such as    methylene chloride or carbon tetrachloride in the presence of a base    such as 2,4,6-collidine, triethylamine or pyridine at a reaction    temperature within the range of −78° C. to room temperature.-   (vii) Conversion of the compound of formula XX to a compound of    formula XXI may be performed by-   a) hydrogenation using a catalyst such as palladium, platinum,    rhodium or nickel in a suitable solvent such as acetic acid or    ethanol at a reaction temperature between +20° C. and +120° C., or-   b) reaction in a suitable solvent such as methanol in the presence    of ammonium formate and Pd/C at a reaction temperature between    +20° C. and reflux.    3. In the Case where Y is CONR₂ and X is N-   (i) Nitration of a compound of formula XXII either as a racemate    (described in: Thorberg S-O.; Hall H.; Åkesson C.; Svensson K.;    Nilsson J. L. G. Acta Pharm. Suec. 1987, 24(4), 169-182), or as an    enantiomer to obtain a compound of formula XXIII,    where R_(d) is C₁-C₆ alkyl, may be carried out by aromatic    electrophilic substitution using a suitable nitration reagent such    as nitric acid or nitric acid and sulfuric acid in a suitable    solvent, e.g. acetic acid, acetic anhydride or water, at a reaction    temperature between −20° C. and room temperature.-   (ii) Demethylation of the compound of the formula XXIII to obtain a    compound of formula XXIV    may be carried out by treating the compound with an acidic reagent    such as aqueous HBr, HI, HBr/CH₃COOH, BBr₃, AlCl₃, pyridine-HCl or    with a basic nucleophilic reagent such as CH₃C₆H₄S⁻ or C₂H₅S⁻.    Suitable solvents may be methylene chloride or chloroform and the    reaction may occur between −78° C. and +60° C.

During the demethylation of XXIII, hydrolysis of the ester may occur andthe acid function could then be converted back to the ester by methodsknown by a person skilled in the art (See T. W. Greene,Wiley-Interscience, New York, 1991).

-   (iii) Conversion of the compound of formula XXIV to a compound of    formula XXV    may be carried out by the reaction with an activated    trifluoromethanesulfonic reagent e.g. trifluoromethanesulfonic    anhydride in a suitable solvent such as methylene chloride,    chloroform or carbon tetrachloride in the presence of a suitable    base such as triethylamine, pyridine or 2,4,6-collidine at a    reaction temperature between −78° C. and room temperature.-   (iv) Conversion of the compound of formula XXV to a compound of    formula XXVI may be carried out by-   a) hydrogenation using a catalyst containing palladium, platinum or    nickel in a suitable solvent such as ethanol, methanol or acetic    acid and at a reaction temperature between +20° C. and +120° C. or-   b) reaction in a suitable solvent such as methanol in the presence    of a ammonium formate such as triethyl ammonium formate and Pd/C and    at a reaction temperature between +20° C. and reflux.-   (v) Conversion of the compound of formula XXVI to a compound of    formula XXVII    may be carried out by reaction of compound XI    where Lg denotes a leaving group, e.g. a halogen such as chlorine,    bromine or iodine, or an alkane- or arenesulfonyloxy group such as    p-toluenesulfonyloxy group and R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆    cycloalkyl. The process may be carried out in a suitable solvent    such as ethanol, butanol, N,N-dimethylformamide, acetonitrile or a    mixture of water and acetonitrile with a suitable base, e.g. K₂CO₃,    NaHCO₃ or KOH, and the reaction may occur between +20° C. and    +150° C. During the cyclization reaction of XXVI, hydrolysis of the    ester may occur.-   (vi) Hydrolysis of a compound of formula XXVII may be carried out    under acidic conditions using acids such as H₂SO₄, HCl, HBr, in a    suitable solvent such as H₂O, ethanol, methanol, acetic acid or    mixtures thereof at a temperature between +20° C. and reflux or    under basic conditions using bases such as NaOH or KOH in a suitable    solvent such as H₂O, ethanol, methanol or mixtures thereof at a    temperature between +20° C. and reflux, resulting in a compound of    formula XXVIII, where R₁ is hydrogen, C₁-C₆ alkyl or C₃-C₆    cycloalkyl.-   (vii) When R₁ is hydrogen, protection of a compound of formula    XXVIII as a compound of formula XXIX where R_(C) is a protecting    group    may be carried out by the reaction with a suitable protecting    reagent such as di-tert-butyl dicarbonate in a suitable solvent,    e.g. methylene chloride or chloroform, with a suitable base such as    triethylamine or K₂CO₃ and at a temperature between −20° C. and +60°    C.    4.-   (i) Conversion of a compound of formula XXX to a compound of formula    XXXI    may be carried out by-   a) hydrolysis of the nitrile in compound of formula XXX in a    suitable solvent such as aqueous methanol or aqueous ethanol in the    presence of a suitable base such as NaOH or KOH at a reaction    temperature between room temperature and reflux, followed by-   b) hydrolysis of the above formed amide and the ketal under acidic    conditions in a suitable solvent such as aqueous methanol, aqueous    ethanol or water in the presence of a suitable acid such as HCl or    HBr at a reaction temperature between room temperature and reflux.-   (ii) Conversion of a compound of formula XXXI to a compound of    formula XXXII    may be carried out by reaction with a suitable azide such as sodium    azide in a suitable acid or mixtures of acids such as H₂SO₄ and    acetic acid at a reaction temperature between 0° C. and +50 C.-   (iii) Conversion of a compound of formula XXXIII to a compound of    formula XXXIV    may be carried out by reaction with 1-benzylpiperazine in a suitable    solvent such as N,N-dimethylformamide, dimethylsulfoxide or    acetonitrile in the presence of a suitable base such as KOH or K₂CO₃    at a reaction temperature between +50° C. and +150° C.-   (iv) Hydrolysis of a compound of formula XXXIV to a compound XXXV    may be carried out under acidic conditions using acids such as    H₂SO₄, HCl or HBr in a suitable solvent, e.g. H₂O, ethanol, methanol    or mixtures thereof, and the reaction may occur between +20° C. and    +100° C. or under basic conditions using bases such as NaOH or KOH    in a suitable solvent, e.g. H₂O, ethanol, methanol or mixtures    thereof, and the reaction may occur between +20° C. and +100° C.-   (v) Halogenation of a compound of formula XXXVI to a compound of    formula XXXVII where Hal denotes bromine, chlorine or iodine may be    performed by a reagent such as ICl or Br₂, Cl₂ or SO₂Cl₂ with a    suitable base such as sodium acetate in a suitable solvent such as    acetic acid at a reaction temperature between +20° C. and +50° C.-   (vi) Conversion of a compound of formula XXXVII to a compound of    formula XXXVIII    may be carried out by a metal-halogen exchange, in an appropriate    anhydrous solvent such as tetrahydrofuran or diethyl ether using a    suitable alkyl-lithium or metal, e.g. butyllithium, lithium or    magnesium turnings, followed by treatment with carbon dioxide at a    reaction temperature between −78° C. and room temperature.    Methods of Preparation of End Products

Another object of the invention is a process A(i), A(ii), A(iii), B(i),B(ii) or C for the preparation of the compound of general formula I by

A(i)

acylation, in the case when R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl, Y isNR₂CO, R₂ is hydrogen and X and R₃ are as defined in general formula Iabove, of a compound of formula A,

with an activated carboxylic acid R₃—COLg₁ where Lg₁ is a leaving groupor by using a carboxylic acid R₃—COOH with an activating reagent.

Thus, the acylation according to the process A(i) may be carried outwith an appropriate activated carboxylic acid, R₃COLg₁ where R₃ is asdefined above and Lg₁ is a leaving group, such as halogen, e.g.chlorine, in a suitable solvent such as methylene chloride or chloroformwith a suitable base, e.g. a trialkylamine such as triethylamine, at atemperature between −20° C. and reflux temperature or by using acarboxylic acid, R₃COOH wherein R₃ is as defined above with anactivating reagent, e.g. N,N′-carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with asuitable base such as N-methylmorpholine in a suitable solvent such asN,N-dimethylformamide or tetrahydrofuran and the reaction may beconducted at a temperature between +20° C. and +150° C.

A(ii)

acylation, in the case when R₁ is hydrogen, Y is NR₂CO, R₂ is hydrogen,R_(c) is a protecting group and X and R₃ are as defined in generalformula I above, of a compound of formula B

with an activated carboxylic acid R₃—COLg₁ where Lg₁ is a leaving groupor by using a carboxylic acid R₃—COOH with an activating reagent,followed by the removal of the protecting group R_(c);

Thus, the acylation according to the process A(ii) may be carried outwith an appropriate activated carboxylic acid, R₃COLg₁ where R₃ is asdefined above and Lg₁ is a leaving group, such as halogen, e.g.chlorine, in a suitable solvent such as methylene chloride or chloroformwith a suitable base, e.g. a trialkylamine such as triethylamine, or byusing a carboxylic acid, R₃COOH where R₃ is defined as above, with anactivating reagent, e.g. N,N′-carbonyldiimidazole,N,N′-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with asuitable base such as N-methylmorpholine in a suitable solvent such asN,N-dimethylformamide or tetrahydrofuran and the reaction may beconducted at a temperature between +20° C. and +150° C., followed byremoval of the protecting group R_(c) by hydrolysis in a suitablesolvent such as methylene chloride or chloroform with a suitable acidsuch as trifluoroacetic acid at a temperature between +20° C. and +60°C.

A(iii)

debenzylation, in the case when R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl, Xand R₂ is as defined in general formula I above and R₉ below is C₁-C₆alkyl, C₃-C₆ cycloalkyl, (CH₂)_(m)OH wherein m is 2-6 or COR₈, of acompound of formula Ia, followed by a) hydrogenation, b) alkylation, c)alkylation and removal of a protecting group or d) acylation;

Thus, in the case when R₉ is H the hydrogenation a) above of a compoundof formula Ia may be carried out by using a catalyst such as palladium,platinum, rhodium or nickel in a suitable solvent such as acetic acid orethanol at a reaction temperature between +20° C. and +120° C., orreaction in a suitable solvent such as methanol in the presence ofammonium formate and Pd/C at a reaction temperature between +20° C. andreflux.

In the case when R₉ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl the debenzylationis followed by the alkylation b) above using a suitable alkylationreagent such as R₁-Lg where Lg is a suitable leaving group, e.g. ahalogen such as chlorine, bromine or iodine, or an alkane- orarenesulfonyloxy group such as a p-toluenesulfonyloxy group and R₁ isC₁-C₆ alkyl. The reaction may be carried out in a suitable solvent suchas N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofliran witha suitable base such as K₂CO₃, NaHCO₃, NaOH or a trialkylamine such astriethylamine. The reaction may be conducted at a temperature between+20° C. and +120° C. or, reductive alkylation with a compound R₁—CHO,where R₁ is hydrogen or C₁-C₅ alkyl, or with a C₃-C₆ cyclic ketone, inthe presence of a reductive agent such as sodium cyanoborohydride,sodium borohydride or catalytically with H₂ and a suitable catalystcontaining palladium, platinum, rhodium or nickel in a suitable solvent,e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor suchas p-toluenesulfonic acid can be used to catalyze the formation of theimine/enamine and adjustment of pH to slightly acidic by an appropriateacid such as acetic acid may speed up the reaction.

In the case when R₉ is (CH₂)_(m)OH and m is 2-6, the debenzylation isfollowed by the alkylation c) above by using a suitable alkylationreagent such as BnO(CH₂)_(m)Lg where Lg is a suitable leaving group,e.g. a halogen such as chlorine, bromine or iodine, or an alkane- orarenesulfonyloxy group such as a p-toluenesulfonyloxy group and R₁ isC₁-C₆ alkyl. The reaction may be carried out in a suitable solvent suchas N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran witha suitable base such as K₂CO₃, NaHCO₃, NaOH or a trialkylamine such astriethylamine and may be conducted at a temperature between +20° C. and+120° C. The reaction is followed by removal of a protecting group, suchas a benzyl group, by hydrogenation using a catalyst such as palladium,platinum, rhodium or nickel in a suitable solvent such as acetic acid orethanol at a reaction temperature between +20° C. and +120° C., orreaction in a suitable solvent such as methanol in the presence ofammonium formate and Pd/C at a reaction temperature between +20° C. andreflux.

In the case when R₉ is COR₈ the debenzylation is followed by theacylation d) above by using an appropriate activated carboxylic acid,R₈COLg₁ where R₈ is as defined above and Lg₁ is a leaving group, such ashalogen, e.g. chlorine, in a suitable solvent such as methylenechloride, chloroform or N,N-dimethylformamide with a suitable base, e.g.a trialkylamine such as triethylamine or by using a carboxylic acid,R₆COOH where R₆ is defined as above, with an activating reagent, e.g.N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide ordiphenylphosphinic chloride, with a suitable base such asN-methylmorpholine in a suitable solvent such as N,N-dimethylformamideor tetrahydrofuran and the reaction may be conducted at a temperaturebetween +20° C. and +150° C.

B(i)

reacting, in the case when R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl, Y isCONR₂, X, R₂ and R₃ are as defined in general formula I above, anactivated carboxylic acid of a compound of formula C,

with an aniline or amine HNR₂R₃.

Thus, conversion according to the process B(i) of a compound of formulaC may be carried out by activation of the acid function of a compound asan acid halide such as an acid chloride or by using an activatingreagent such as N,N′-carbonyldiimidazole orN,N-dicyclohexylcarbodiirnide in a suitable solvent, e.g. methylenechloride, chloroform, toluene, N,N-dimethylformamide, dioxane ortetrahydrofuran, followed by the addition of an appropriate amine oraniline HNR₂R₃ and the reaction may occur between 0° C. and +120° C.

B(ii)

reacting, in the case when R₁ is hydrogen, Y is NR₂CO, R_(c) is aprotecting group and X, R₂ and R₃ are as defined in general formula Iabove, an activated carboxylic acid of a compound of formula D,

with an aniline or amine HNR₂ R₃, followed by removal of the protectinggroup R_(c).

Thus, conversion according to the process B(ii), of a compound offormula D, may be carried out by activation of the acid function of acompound as an acid halide such as an chloride or by using an activatingreagent such as N,N′-carbonyldiimidazole or N,N-dicyclohexylcarbodiimidein a suitable solvent, e.g. methylene chloride, chloroform, toluene,N,N-dimethylformamide, dioxane or tetrahydrofuran, followed by theaddition of an appropriate amine or aniline HNR₂R₃ and the reaction mayoccur between 0° C. and +120° C., followed by removal of the protectinggroup R_(c) by methods known by a person skilled in the art such ashydrolysis in a suitable solvent such as methylene chloride orchloroform with a suitable acid, e.g. trifluoroacetic acid, at atemperature between +20° C. and +60° C.

C

reaction, in the case when R₁ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl, Y isNR₂CONR₂, R₂ is hydrogen and X and R₃ are as defined in general formulaI above, a compound of formula A,

with a suitable azide in the presence of a carboxylic acid, R₃COOH.

Thus, reaction according to the process C may be carried out with anappropriate azide such as diphenylphosphoryl azide in the presence of acarboxylic acid, R₃COOH where R₃ is as defined above in a suitablesolvent such as acetonitrile and the reaction may be conducted at atemperature between +20° C. and reflux temperature.

Intermediates

Another object of the invention is a compound having the formula

wherein

-   X═N or CH;-   Z=NH₂ or COOH;-   R₁ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl.

The invention is illustrated but not restricted to the following workingexamples.

WORKING EXAMPLES Example 1(R)-3-N,N-Dibenzylamino-5-methoxy-3,4-dihydro-2H-1-benzopyran

(R)-3-Amino-5-methoxy-3,4-dihydro-2H-1-benzopyran (2.6 g, 14 mmol),K₂CO₃ (7.0 g, 51 mmol), benzylbromide (6.0 g, 35 mmol) and a catalyticamount of potassium iodide were mixed in acetonitrile (100 mL) undernitrogen. The reaction mixture was refluxed for 72 h. The solvent wasremoved in vacuo, and the residue was partitioned between diethyl etherand a 2 M NH₃ solution. The layers were separated, and the aqueous phasewas extracted twice with diethyl ether. The ethereal layers werecombined and dried (MgSO₄). The solvent was removed in vacuo to give ayellow oily residue which was purified by flash chromatography on silicagel (eluent: methylene chloride) affording 3.2 g (64% yield) of thetitle compound: EIMS (70 eV) m/z (relative intensity) 359 (91, M⁺). TheHCl salt was precipitated from diethyl ether at 0° C. and thenrecrystallized from ethanol/diethyl ether. The crystals were hygroscopicand started to melt at 100° C. and melted finally between 118 and 120°C.; [α]²¹ _(D) −20° (c 0.3, methanol).

Example 2 (S)-3-N,N-Dibenzylamino-5-methoxy-3,4-dihydro-2H-1-benzopyran

The title compound was synthesized according to the procedure describedfor its corresponding (R)-enantiomer: [α]² _(D) (measured on the freebase) +116° (c 1.0, chloroform).

Example 3 (R)-3-N,N-Dibenzylamino-5-hydroxy-3,4-dihydro-2H-1-benzopyran

(R)-3-N,N-Dibenzylamino-5-methoxy-3,4-dihydro-2H-1-benzopyranhydrochloride (1.6 g, 4.0 mmol) was dissolved in methylene chloride (40mL) under nitrogen, and the solution was cooled to −70° C. A solution ofboron tribromide (1.8 g, 7.3 mmol) in methylene chloride (25 mL) wasadded dropwise over 5 min. The temperature was then allowed to slowlyreach 0° C., and the reaction was stirred overnight. The reactionmixture was carefully poured into a saturated NaHCO₃ solution withstirring. The layers were separated and the aqueous phase was extractedthree times with methylene chloride. The organic layers were combinedand dried (MgSO₄). The solvent was removed in vacuo to give a brownishoily residue which was purified by flash chromatography on silica gel(eluent: methylene chloride) affording 0.14 g (98% yield) of the titlecompound: [α]²¹ _(D −)94° (c 0.1, methanol); EIMS (70 eV) m/z (relativeintensity) 345 (100, M⁺).

Example 4 (S)-3-N,N-Dibenzylamino-5-hydroxy-3,4-dihydro-2H-1-benzopyran

The title compound was synthesized according to the procedure describedfor its corresponding (R)-enantiomer: [α]²¹ _(D) +109° (c 1.0,chloroform).

Example 5(R)-2-(3-N,N-Dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yloxy)-2-methylpropanamide

(R)-3-N,N-Dibenzylamino-5-hydroxy-3,4-dihydro-2H-1-benzopyran (35.4 g,100 mmol) was dissolved in anhydrous 1,4-dioxane (350 mL) undernitrogen. A dispersion of sodium hydride (60-65% in oil, 5.33 g, 130mmol) was added in portions. The mixture was stirred for 2 h at roomtemperature. 2-Bromo-2-methylpropanamide (17.9 g, 110 mmol; described inCoutts, I. G. C.; Southcott, M. R. J Chem. Soc. Perkin Trans. 1 1990,767-771) was added to the dark greenish solution and was heated atreflux with stirring for 3 h. After cooling, a small amount of water wasadded, the solution was decanted, and the solvent was removed in vacuo.The residue was partitioned between ethyl acetate (350 mL) and asaturated NaHCO₃ solution (50 mL). The organic layer was dried (MgSO₄),and the solvent was removed in vacuo to give a brownish residue whichwas chromatographed on a short column of silica gel (eluent:hexane/ethyl acetate; 55:45) affording 27.6 g (64% yield) of the titlecompound as a white solid: mp 132-134° C.; [α]²² _(D) −92° (c 1.0,chloroform); EIMS (70 eV) m/z (relative intensity) 430 (6, M⁺).

Example 6(S)-2-(3-N,N-Dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yloxy)-2-methylpropanamide

The title compound was synthesized according to the procedure describedfor its corresponding (R)-enantiomer: [α]²¹ _(D)+99° (c 1.0,chloroform).

Example 7 (R)-5-Amino-3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran

1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (31 mL) was added toa stirred solution of(R)-2-(3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yloxy)-2-methylpropanamide(31.0 g, 72.0 mmol) in anhydrous N,N-dimethylformamide (310 mL) undernitrogen. Sodium hydride (60-65% in oil, 5.76 g, 144 mmol) was added inportions. The reaction mixture was heated at 100° C. and was stirred for16 h. The mixture was then allowed to cool, and the solution waspartitioned between ethyl acetate (500 mL) and a 2 M NH₃ solution (300mL). The layers were separated, and the aqueous layer was extracted withethyl acetate (150 mL). The combined organic layers were dried (MgSO₄)and concentrated in vacuo to give a brownish oil. The obtained materialwas dissolved in ethanol (400 mL). A 6 M HCl solution (500 mL) wasadded, and the reaction mixture was heated to reflux at 85° C. Afterstirring overnight, the mixture was allowed to cool to 35° C., theethanolic solvent was concentrated in vacuo, and toluene was added tothe residual aqueous solution. The mixture was cooled on ice, and asolution of conc. NH₃ was slowly added with stirring. An almostinsoluble material formed. The alkaline two-phase system was transferredto a separatory fuinnel, and the insoluble material was treated with a 2M NH₃ solution and ethyl acetate. Eventually, all material was dissolvedand it was combined with the already obtained two-phase mixture. Thelayers were separated, and the aqueous layer was extracted with anotherportion of ethyl acetate. The combined organic layers were dried(MgSO₄), and the solvent was removed in vacuo to give a brownish oilwhich was purified on a short column of silica gel (eluent: hexane/ethylacetate; 80:20) affording 19.0 g (72% yield) of the desired compound asa light yellow oil. The product slowly crystallized upon standing in therefrigerator: mp 99-101° C.; [α]²¹ _(D)−131° (c 1.0, chloroform); EIMS(70 eV) m/z (relative intensity) 344 (38, M⁺).

Example 8 (S)-5-Amino-3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran

The title compound was synthesized according to the procedure describedfor its corresponding (R)-enantiomer: [α]²¹ _(D)+123° (c 1.0,chloroform). An analytical sample was recrystallized from diethylether/petroleum ether: mp 101-103° C.

Example 9(R)-3-N,N-Dibenzylamino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran

To a solution of(R)-5-amino-3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran (2.86 g,8.30 mmol) in a mixture of 15% water in acetonitrile (120 mL) were addedsodium iodide (69 mg, 0.42 mmol) and N-methyl-bis(2-chloroethyl)aminehydrochloride (3.20 g, 16.6 mmol) with stirring. The clear solution washeated at reflux. After 7 h of stirring, NaHCO₃ (700 mg, 8.30 mmol) wasadded, and the reaction mixture was stirred for an additional 11 h.Another portion of NaHCO₃ (700 mg, 8.30 mmol) was added followed bycontinued reflux. After 6 h, a final portion of NaHCO₃ (350 mg, 4.15mmol) was added, and the reaction mixture was stirred for 6 h more (30 hin all). The mixture was cooled on an ice-bath, and a 2 M NaOH solution(20 mL) was added with stirring. The two-phase system was stirred for 10min after which the solvents were removed under reduced pressure until aprecipitation occurred. The aqueous residue was extracted with diethylether (150 mL), the layers were separated, and the aqueous layer wasextracted with diethyl ether (2+50 mL). The combined ethereal layerswere dried (MgSO₄), and the solvent was removed in vacuo. The crudeproduct was purified by column chromatography on silica (eluent:chloroform/ethanol; 95.5:4.5+0.5% conc. NH₃) affording 2.39 g (67%yield) of the title compound as a colorless oil: [α]²¹ _(D) −45° (c 1.0,chloroform); EIMS (70 eV) m/z (relative intensity) 427 (0.3, M⁺).

Example 10(S)-1-(3-N,N-Dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yl)-4-methylpiperazine-2,6-dione

To a dispersion of N-methyliminodiacetic acid (6.90 g, 46.9 mmol) inanhydrous tetrahydrofuran (575 mL) was added 1,1′-carbonyldiimidazole(15.2 g, 93.9 mmol), and the mixture was heated at reflux for 2 h undernitrogen. A solution of(S)-5-amino-3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran (15.0 g,42.7 mmol) in tetrahydrofuran (120 mL) was added with stirring over 0.5h. The reaction mixture was heated at reflux for 28 h, then allowed tocool, and the solvent was removed in vacuo. The residue was purified ona short column of silica gel (eluent: methylene chloride and ethylacetate) affording 14.1 g (71% yield) of the title compound as a lightyellow solid: mp sinters >60° C.; [α]²¹ _(D) +89° (c 1.0, chloroform);EIMS (70 eV) m/z (relative intensity) 455 (8, M⁺).

Example 11(S)-3-N,N-Dibenzylamino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran

To a stirred solution of(S)-1-(3-N,N-dibenzylamino-3,4-dihydro-2H-1-benzopyran-5-yl)-4-methylpiperazine-2,6-dione (25.4 g, 55.8 mmol) in anhydrous diethyl ether (800 mL)was added lithium aluminum hydride (9.30 g, 246 mmol) in portions. Thereaction mixture was heated to reflux for 6.5 h under nitrogen and wasstirred overnight at room temperature. The mixture was cooled(ice-bath), and water (10 mL) was added followed by a 15% aqueoussolution of NaOH (10 mL) and another portion of water (30 mL). Theprecipitate was filtered off and washed with several portions of warmtetrahydrofuran. The organic layers were combined, and the solvent wasremoved in vacuo. The residue was purified by column chromatography onsilica (eluent: chloroform/ethanol; 95:5+0.5% conc. NH₃) affording 13.6g (57% yield) of the title compound as a light yellow oil: [α]²⁵ _(D)+63° (c 1.0, methanol); EIMS (70 eV) m/z (relative intensity) 427 (5,M⁺).

Example 12(R)-3-Amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran

To a solution of(R)-3-N,N-dibenzylamino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran(2.34 g, 5.47 mmol) in anhydrous methanol (100 niL) were added palladium(10%) on activated carbon (0.86 g) and ammonium formate (2.76 g, 43.8mmol) under nitrogen. The reaction mixture was heated at 50° C. withstirring overnight. The solution was filtered through Celite®, and thesolvent was removed in vacuo. The residue was partitioned between a 2 MNH₃ solution (20 mL) and ethyl acetate (100 mL). The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (3+50mL). The combined organic phases were dried (Na2SO4), and the solventwas removed in vacuo to give 1.21 g (90% yield) of the title compound asa pale yellow oil: [α]²¹ _(D) +15° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 247 (6, M⁺).

Example 13(S)-3-Amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran

The title compound was synthesized according to the procedure describedfor its corresponding (R)-enantiomer: [α]²¹ _(D) −15° (c 1.0,chloroform).

Example 14(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-morpholinobenzamide

A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mmol; described in:Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10),2060-2064) and 1,1′-carbonyldiimidazole (310 mg, 1.92 mmol) in anhydrousN,N-dimethylformamide (12 mL) was stirred at 75° C. for 30 min. Themixture was allowed to cool after which a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (430mg, 1.74 mmol) in N,N-dimethylformamide (8 ifL) was added. The reactionmixture was stirred at room temperature for 3 days. Another portion of1,1′-carbonyldiimidazole (57 mg, 0.35 mmol) was added, and the mixturewas stirred for an additional 3.5 h. The solvent was removed in vacuo,and the residue was purified by column chromatography on silica (eluent:chloroform/ethanol; 93:7+0.5% NH3) affording 513 mg (68% yield) of thetitle compound as a white solid: mp 210-212° C.; [α]²² _(D) −145° (c1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 436 (65, M⁺).

Example 15(R)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-morpholinobenzamide

The title compound was synthesized according to the procedure describedfor its corresponding (S)-enantiomer: [α]²¹ _(D) +145° (c 1.0,chloroform).

Example 16(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2-1-benzopyran-3-yl]-4-piperidinobenzamide

A suspension of 4-piperidinobenzoic acid (276 mg, 1.35 mmol; describedin: Weringa, W. D.; Janssen, M. J. Rec. Trav. Chim. Pays-Bas 1968,87(12), 1372-1380) and 1,1′-carbonyldiimidazole (229 mg, 1.41 mmol) inanhydrous N,N-dimethylformamide (11 mL) was placed in an oil bath at 75°C. After 45 min of stirring, the mixture was allowed to cool. A solutionof (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran(317 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL) was added, and themixture was stirred at room temperature for 40 h. Another portion of1,1′-carbonyldiimidazole (83 mg, 0.51 mmol) was added, and the reactionwas stirred for 3 days. At this time, the reaction was not complete anda final amount of 1,1′-carbonyldiimidazole (42 mg, 0.25 mmol) was added.The reaction mixture was heated for 3 h at 50° C. after which thesolvent was removed in vacuo. The residue was purified by columnchromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% NH₃)affording 202 mg (36% yield) of the title compound as a white solid: mp178-180° C.; [α]²² _(D)−159° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 434 (35, M⁺).

Example 17(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-butoxybenzamide

A solution of 4-butoxybenzoic acid (650 mg, 3.35 mmol) in thionylchloride (13 mL) was heated at 50° C. for 15 min after which the mixturewas allowed to reach room temperature. The excess of thionyl chloridewas removed under reduced pressure, and the residue was evaporated withtwo portions of toluene. The acid chloride was obtained as a brownishoil. A portion of the acid chloride (150 mg, 0.705 mmol) was dissolvedin methylene chloride (5 mL) and added to an ice-cooled solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (159mg, 0.643 mmol) and triethylamine (134 μL, 0.960 mmol) in anhydrousmethylene chloride (20 mL). The ice-bath was removed, and thetemperature was allowed to reach room temperature. The reaction mixturewas washed with a saturated NaHCO₃ solution (10 mL), dried (MgSO₄), andthe solvent was removed in vacuo. The residue was purified by columnchromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc.NH₃) affording 200 mg (74% yield) of the title compound as a whitesolid: mp 192-193.6° C.; [α]²² _(D) −114° (c 1.0, chloroform); EIMS (70eV) m/z (relative intensity) 423 (52, M⁺).

Example 18(R)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-butoxybenzamide

The title compound was synthesized according to the procedure describedfor its corresponding (S)-enantiomer: [α]²¹ _(D) +104° (c 1.0,chloroform).

Example 19(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide

A mixture of 4-trifluoromethylbenzoic acid (195 mg, 1.02 mmol) inthionyl chloride (5 mL) was heated at 50° C. for 20 min and then toreflux for 10 min. The mixture was allowed to cool after which theexcess of thionyl chloride was removed in vacuo, and the residue wasevaporated with two portions of toluene. The acid chloride was thendissolved in anhydrous methylene chloride (5 mL) and added to anice-cooled solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrousmethylene chloride (20 mL) with stirring. The reaction mixture wasallowed to reach room temperature and was washed with a saturated NaHCO₃solution. After drying (MgSO₄) and evaporation of the solvent in vacuo,a crude product was obtained which was purified by column chromatographyon silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH₃). Thisprocedure gave 214 mg (55% yield) of the title compound as a whitesolid: mp 212-214° C.; [α]²² _(D) −73° (c 1.0, chloroform); EIMS (70 eV)m/z (relative intensity) 419 (100, M⁺).

Example 20(R)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide

The title compound was synthesized according to the procedure describedfor its corresponding (S)-enantiomer: [α]²¹ _(D) +74° (c 1.0,chloroform).

Example 21(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-2,4-dimethoxybenzamide

A solution of 2,4-dimethoxybenzoic acid (185 mg, 1.01 mmol) in thionylchloride (5 mL) was heated at 55° C. for 15 min. The excess of thionylchloride was removed in vacuo, and the residue was evaporated with twoportions of toluene. The acid chloride was then dissolved in anhydrousmethylene chloride (5 mL) and added to an ice-cooled solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (228mg, 0.920 mmol) in anhydrous methylene chloride (20 niL) with stirring.The precipitated product was dissolved by the addition of triethylamine(193 μL, 1.38 mmol) to give a clear light yellow solution. The ice-bathwas removed, and the reaction mixture was stirred at room temperaturefor 1 h. The mixture was washed with a saturated NaHCO₃ solution, dried(MgSO₄), and the solvent was removed in vacuo. The residue was purifiedby column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH₃) affording 268 mg (71% yield) of the title compound asan oil: [α]²¹ ^(D) −91° (c 1.0, chloroform); EIMS (70 eV) m/z (relativeintensity) 411 (4, M⁺). The base (238 mg, 0.578 mmol) was dissolved inanhydrous diethyl ether (10 mL) under nitrogen and was cooled on anice-bath. A solution of HCl in diethyl ether (3 M, 0.5 mL), diluted withdiethyl ether (5 mL), was added dropwise with stirring. The HCl salt wasfiltered, washed with diethyl ether, and dried in vacuo affording 187 mg(69% yield) of the product as a white powder: mp sinters >44° C.

Example 22(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-N,N-diethylaminobenzamide

A solution of 4-diethylaminobenzoic acid (189 mg, 0.978 mmol) and1,1′-carbonyldiimidazole (166 mg, 1.02 mmol) in anhydrousN,N-dimethylformamide (5 mL) was stirred at 75° C. for 45 min. Themixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230mg, 0.930 mmol) in N,N-dimethylformamide (8 mL) was added. The reactionmixture was stirred at room temperature for 7 days. The solvent wasremoved in vacuo, and the residue was purified by column chromatographyon silica (eluent: chloroform/ethanol; 92:8+0.5% NH₃) affording 234 mg(60% yield) of the title compound as a white solid: mp 218-219.6° C.;[α]²¹ _(D) −178° (c 1.0, chloroform); EIMS (70 eV) m/z (relativeintensity) 422 (29, M⁺).

Example 23(R)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-N,N-diethylaminobenzamide

The title compound was synthesized according to the procedure describedfor its corresponding (S)-enantiomer: [α]²¹ _(D) +172° (c 1.0,chloroform).

Example 24(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-furan-2-carboxamide

To an ice-cooled stirred solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrousmethylene chloride (10 mL) was added 2-furoyl chloride (101 μL, 1.02mmol) under nitrogen. The ice-bath was removed, and the reaction mixturewas allowed to reach room temperature. The mixture was washed with a 2 MNH₃ solution, dried (MgSO₄), and the solvent was removed in vacuo. Theremains was purified on a chromatotron (accelerated thin layerchromatography, eluent: chloroform/ethanol; 92:8+0.5% conc. NH₃)affording 249 mg (79% yield) of the title compound as a white solid: mpsinters >50° C.; [α]²¹ _(D) −83° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 341 (52, M⁺).

Example 25(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-N,N-dimethylaminobenzamide

A solution of 4-dimethylaminobenzoic acid (190 mg, 1.15 mmol) and1,1′-carbonyldiimidazole (205 mg, 1.26 mmol) in anhydrousN,N-dimethylformamide (5 mL) was stirred at 75° C. for 35 min. Themixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (271mg, 1.10 mmol) in N,N-dimethylformamide (5 mL) was added. The reactionmixture was stirred at room temperature for 4 days. The solvent wasremoved in vacuo, and the residue was purified by column chromatographyon silica (eluent: chloroform/ethanol; 92:8+0.5% NH₃) affording 292 mg(67% yield) of the title compound as a white solid: mp 248-250° C.;[α]²¹ _(D) −175° (c 1.0, chloroform); EIMS (70 eV) m/z (relativeintensity) 394 (46, M⁺).

Example 26(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-pyrrole-2-carboxamide

A mixture of 1,1′-carbonyldiimidazole (360 mg, 1.85 mmol) andpyrrole-2-carboxylic acid (225 mg, 2.03 mmol) in anhydrousN,N-dimethylformamide (8 mL) was stirred at 75° C. for 45 min. Themixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (457mg, 1.85 mmol) in N,N-dimethylformamide (10 mL) was added. The reactionmixture was stirred for 7 days at room temperature under nitrogen. Thesolvent was removed in vacuo, and the residue was extracted with diethylether (50 mL) and water (20 mL). The aqueous layer was extracted withanother portion of diethyl ether (50 mL). The combined ethereal layerswere dried (MgSO₄), and the solvent was removed in vacuo. The residuewas purified by column chromatography on silica (eluent:chloroform/ethanol; 90:10+0.5% conc. NH₃) yielding the title compound asan oil. Evaporation with diethyl ether afforded 300 mg (48% yield) ofthe title compound as a white powder: mp sinters >96° C.; [α]²¹ _(D)−82.8° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 340(10, M⁺).

Example 27(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-5-methylpyridine-3-carboxamide

A solution of 5-methylnicotinic acid (141 mg, 1.03 mmol) and1,1′-carbonyldiimidazole (183 mg, 1.13 mmol) in anhydrousN,N-dimethylformamide (5 mL) was stirred at 75° C. for 55 min. Themixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (232mg, 0.94 mmol) in N,N-dimethylformamide (5 mL) was added. The reactionmixture was stirred at room temperature for 28 h. The solvent wasremoved in vacuo, and the residue was purified by column chromatographyon silica (eluent: chloroform/ethanol; 87:13+0.5% NH₃). The product wascontaminated with a large amount of imidazole which could be removed bythe following procedure: The mixture was dissolved in diethyl ether (100mL), washed with water (2+20 mL) and treated with brine (10 mL). Theethereal layer was dried (MgSO₄), and the solvent was removed in vacuoto give 119 mg (35% yield) of the title compound as a white solid: mpsinters >68° C.; [α]²¹ _(D) −82° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 366 (21, M⁺).

Example 28(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-2,4-bis(trifluoromethyl)benzamide

A solution of 2,4-bis(trifluoromethyl)benzoic acid (195 mg, 0.755 mmol)in thionyl chloride (4 mL) was heated at 55° C. for 45 min. The excessof thionyl chloride was removed in vacuo, and the residue was evaporatedwith two portions of toluene. The acid chloride was then dissolved inanhydrous methylene chloride (5 mL) and added to a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (170mg, 0.687 mmol) and triethylamine (144 μL, 1.03 mmol) in anhydrousmethylene chloride (20 mL) with stirring. The reaction mixture was leftovernight at room temperature and was washed with a 2 M NH₃ solution (10mL) followed by a portion of brine. The organic layer was dried (MgSO₄),and the solvent was removed in vacuo. The residue was purified by columnchromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc.NH₃) affording 100 mg (30% yield) of the title compound as a whitepowder: mp 202-203° C.; [α]²¹ _(D) −51° (c 1.0, chloroform); EIMS (70eV) m/z (relative intensity) 487 (16, M⁺).

Example 29(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-2-hydroxy-4-methoxybenzamide

A solution of 4-methoxy-2-acetoxybenzoic acid (232 mg, 1.10 mmol;described in: Schonhofer, F. Ber Deutsch Chem Ges 1951, 84, 13) inthionyl chloride (5 mL) was heated at 55° C. for 30 min. The excess ofthionyl chloride was removed in vacuo, and the residue was evaporatedwith two portions of toluene. The acid chloride was then dissolved inanhydrous methylene chloride (5 mL) and added to a stirred solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (248mg, 1.00 mmol) and triethylamine (210 μL, 1.50 mmol) in anhydrousmethylene chloride (20 mL). The reaction mixture was stirred at roomtemperature for 2.5 h after which the mixture was washed with asaturated NaHCO₃ solution, dried (MgSO₄), and the solvent was removed invacuo. The residue was dissolved in absolute ethanol (20 mL), and conc.NH₃ (5 mL) was added. The mixture was stirred overnight. The solvent wasremoved in vacuo, and the remains was purified by column chromatographyon silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH₃) affording120 mg (33% yield) of the title compound as a white solid: mpsinters >80° C.; [α]²¹ _(D) −92° (c 1.0, chloroform); EIMS (70 eV) m/z(relative intensity) 397 (27, M⁺).

Example 30(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-Trifluoromethoxybenzamide

A mixture of 4-trifluoromethoxybenzoic acid (254 mg, 1.23 mmol) inthionyl chloride (5 mL) was heated at 60° C. for 25 min. The excess ofthionyl chloride was removed under reduced pressure, and the remainswere evaporated with two portions of toluene. The acid chloride was thendissolved in anhydrous methylene chloride (5 mL) and added to a stirredsolution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (277mg, 1.12 mmol) and triethylamine (234 μL, 1.68 mmol) in methylenechloride (10 mL). The reaction mixture was stirred for 2 h at roomtemperature and was washed with a saturated solution of NaHCO₃. Theorganic layer was dried (MgSO₄), and the solvent was removed in vacuo.The product was purified by column chromatography on silica (eluent:chloroform/ethanol, 92:8+0.5% conc. NH₃) affording 248 mg (51% yield) ofthe title compound as a white solid: mp 192-193. C.; [α]²¹ _(D) −75° (c1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 435 (6, M⁺).

Example 31 4-(4-Piperidon-1-yl)benzoic Acid

A solution of 2 M NaOH (10 mL),4-(8-aza-1,4-dioxaspiro[4,5]dec-8-yl)benzonitrile (820 mg, 3.36 mmol;described in: Taylor E. C.; Skotnicki J. S. Synthesis 1981, 8, 606-608),and ethanol (7.5 mL) was heated at reflux for 3 h. The external heatingwas interrupted, and the reaction mixture was stirred overnight atambient temperature. The ethanolic solvent was removed in vacuo, and theremains were acidified to pH 4 with a 2 M HCl solution followed byextraction with ethyl acetate (50 mL). The layers were separated, and pHwas adjusted to pH 6 with a 2 M NaOH solution followed by anotherextraction with ethyl acetate (50 mL). The combined organic layers wereconcentrated in vacuo, and the solid residue was dissolved in a 6 M HClsolution (10 mL). The reaction mixture was heated at 75° C. for 2.5 hand then at 55° C. overnight. The temperature was raised to 75° C. for 2h, and the reaction mixture was then allowed to cool. The pH wasadjusted to pH 4, and the solution was extracted with ethyl acetate (50mL). The layers were separated, and another extraction was made at pH 5.The combined organic layers were dried (MgSO₄), and the solvent wasremoved in vacuo. The crude product was recrystallized from ethylacetate affording 300 mg (41% yield) of the title compound as yellowishcrystals: mp sinters>215° C.; EIMS (70 eV) m/z (relative intensity) 219(100, M⁺).

Example 32(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(4-piperidon-1-yl)benzamide

A solution of 1,1′-carbonyldiimidazole (116 mg, 0.716 mmol) and4-(4-piperidon-1-yl)benzoic acid (150 mg, 0.683 mmol) in anhydrousN,N-dimethylformamide (5 mL) was stirred at 75° C. for 50 min. Themixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (161mg, 0.651 mmol) in N,N-dimethylformamide (4 mL) was added. The reactionmixture was stirred at room temperature for 8 days. The solvent wasremoved in vacuo, and the residue was purified by column chromatographyon silica (eluent: chloroform/ethanol, 90:10+0.5% conc. NH₃) affording54 mg (19% yield) of the title compound as a white solid: mp 222-225° C.(decomposes); [α]²² _(D) −136° (c 0.30, chloroform); TSPMS (70 eV) m/z449 (M+1).

Example 33(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-morpholinobenzenesulfonamide

To a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (120mg, 0.485 mmol) in anhydrous methylene chloride (10 mL) were addedtriethylamine (81 μL, 0.582 mmol) and 4-(4-morpholinyl)benzenesulfonylchloride (140 mg, 0.534 mmol; described in: Galliani, G. Eur. Pat. Appl.EP 335, 758, 1989, Chem. Abstr. 1990, 112, 98374d [125393-22-8]). Thereaction mixture was stirred at room temperature for 4 h, washed with a2 M NH₃ solution, dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica (eluent:chloroform/ethanol, 90:10+0.5% conc. NH₃) affording 141 mg (61% yield)of the title compound as a white solid: mp sinters >100° C.; [α]²² _(D)+10° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 472 (56,M⁺).

Example 34 4-(Hexahydro-1,4-diazepin-5-on-1-yl)benzoic Acid

A solution of 4-(piperidon-1-yl)benzoic acid (281 mg, 1.28 mmol), conc.acetic acid (2 mL), and conc. H₂ SO₄ (1 mL) was cooled to 5° C. Sodiumazide (92 mg, 1.41 mmol) was added, and the reaction mixture was stirredat 7° C. for 42 h. A solution of 2 M NaOH was added to pH 5, and theresulting precipitate was filtered and washed with several portions ofice-cooled water. Drying in vacuo afforded 272 mg (91% yield) of thetitle compound as a white solid: mp 285-286° C.; EIMS (70 eV) m/z(relative intensity) 234 (66, M⁺).

Example 35(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(hexahydro-1,4-diazepin-5-on-1-yl)benzamide

A solution of 1,1′-carbonyldiimidazole (151 mg, 0.934 mmol) and4-(hexahydro-1,4-diazepin-5-on-1-yl)benzoic acid (219 mg, 0.934 mmol) inanhydrous N,N-dimethylformamide (7 mL) was stirred at 75° C. for 55 min.The mixture was allowed to cool, and a solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (210mg, 0.85 mmol) in N,N-dimethylformamide (3.5 mL) was added. The reactionmixture was stirred at room temperature for 14 days. The solvent wasremoved in vacuo, and the residue was purified by column chromatographyon silica (eluent: chloroform/ethanol, 90:10+1% conc. NH₁₃). The productwas crystallized from a mixture of chloroform, ethanol, and ethylacetate affording 84 mg (21% yield) of the title compound as whitecrystals: mp 244-247° C. (decomposes); [α]²¹ _(D) −148° (c 0.50,chloroform); TSPMS (70 eV) m/z 464 (M+1).

Example 36(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-N′-(4-morpholino)phenylUrea

To a stirred solution of 4-morpholinobenzoic acid (126 mg, 0.606 mmol)and (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran(150 mg, 0.606 mmol) in acetonitrile (5 mL) was diphenylphosphoryl azide(131 μL, 0.606 mmol) added. The reaction mixture was heated at refluxfor 1.5 h and was then allowed to cool to room temperature overnight.The solvent was removed in vacuo, and the residue was partitionedbetween ethyl acetate and a 2 M NH₃ solution. The organic layer wasdried (MgSO₄), and the solvent was removed in vacuo. The residue waspurified by column chromatography on silica (eluent: chloroform/ethanol,90:10+0.5% conc. NH₃) affording 100 mg (36% yield) of the title compoundas a white solid: mp sinters >118° C.; [α]²¹ _(D) −71° (c 0.5,chloroform); MSTSP 452 (M+1).

Example 37 4-Bromo-3-methoxymorpholinobenzene

To a stirred slurry of 4-(3-methoxyphenyl)morpholine (1.54 g, 7.97 mmol;described in: Skowronska-Ptasinska M.; Verboon W.; Reinhoudt D. N. J.Org. Chem. 1985, 50(15), 2690-8) and sodium acetate (0.784 g, 9.56 mmol)in 1,4-dioxane (100 mL) was added a 0.25 M solution of bromine in1,4-dioxane (35.0 mL, 8.77 mmol) over 45 min. Another portion of thebromine solution (15.0 μL, 4.00 mmol) and sodium acetate (0.523 g, 6.38mmol) were added, and the reaction mixture was heated at 50° C.overnight. The solvent was removed in vacuo, and the residue waspartitioned between diethyl ether (100 mL) and a 2 M NH₃ solution. Thelayers were separated, and the aqueous layer was extracted with diethylether (50 mL). The combined organic layers were dried (MgSO₄), and thesolvent was removed in vacuo. The residue was filtered through a columnof silica gel (eluent: chloroform/ethanol, 1:1+1.5% conc. NH3), and thesolvent was removed in vacuo. The residue was partitioned betweenmethylene chloride and a 2 M NH₃ solution. After drying (MgSO₄) of theorganic layer and removal of the solvent in vacuo, an orange oil wasobtained which was purified by column chromatography on silica (eluent:methylene chloride +0.5% conc. NH₃) affording 450 mg (21% yield) of thetitle compound as a white solid: mp 103.5-104.5° C.; EIMS (70 eV) m/z(relative intensity) 273/271 (56/56, M⁺).

Example 38 2-Methoxy-4-morpholinobenzoic Acid

To a stirred solution of 4-bromo-3-methoxy-1-morpholinobenzene (104 mg,0.382 mmol) in anhydrous tetrahydrofuran (3 mL) at −78° C. was slowlyadded n-butyl lithium (1.3 M solution in hexanes, 325 μL, 0.420 mmol)under nitrogen. The cooling medium was exchanged with an ice-bath, andthe mixture was stirred for 5 min. After cooling again to −78° C.,carbon dioxide from evaporation of dry ice was bubbled through thesolution for 10 min. A precipitate was formed, and the reaction mixturewas allowed to reach room temperature. Diethyl ether and water wereadded. The mixture was extracted, the layers were separated, and theaqueous layer was acidified to pH 4. The dark blue aqueous solution wasextracted several times with diethyl ether and ethyl acetate at pH 4 topH 6. The combined organic layers were dried (MgSO₄), and the solventwas removed in vacuo affording 60 mg (66% yield) of the title compoundas a white solid: mp 158-160° C.; EIMS m/z (relative intensity) 237(100, M⁺).

Example 39(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-2-methoxy-4-morpholinobenzamide

A stirred solution of 1,1′-carbonyldiimidazole (222 mg, 1.37 mmol) and2-methoxy-4-morpholinobenzoic acid (176 mg, 0.740 mmol) in anhydrousN,N-dimethylformamide (5 mL) was heated at 75° C. for 2 h, and was thenallowed to cool. A solution of(S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (183mg, 0.740 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added. Thereaction mixture was stirred at room temperature for 5 days. The solventwas removed in vacuo, and the residue was partitioned between ethylacetate (50 mL) and a 2 M NH₁₃ solution (15 mL). The organic layer wasdried (MgSO₄), and the solvent was removed in vacuo. The residue waspurified by column chromatography on silica (eluent: chloroform/ethanol,93:7+0.5% conc. NH₃) affording 113 mg (30% yield) of the title compoundas an uncolored foam: [α]²¹ _(D) −141° (c 0.5, chloroform); EIMS (70eV)) m/z (relative intensity) 466 (20, M⁺).

Example 40 4-(4-Benzylpiperazin-1-yl)benzonitrile

To a solution of 4-fluorobenzonitrile (3.0 g, 25 mmol) inN,N-dimethylformamide (15 mL) were added 1-benzylpiperazine (4.3 mL, 25mmol) and potassium carbonate (3.4 g, 25 mmol). The reaction mixture wasstirred at 120° C. for 13 h. The solvent was evaporated in vacuo and theresidue was partitioned between ethyl acetate (100 mL) and water (15mL). The aqueous phase was extracted with ethyl acetate (30 mL) and thecombined organic phases were washed twice with brine (10 mL) and dried(MgSO₄). Evaporation of the solvent gave 7.6 g of crude product.Purification of the residue on a silica gel column using ethylacetate/methylene chloride (1:9) as the eluent afforded 4.0 g (59%yield) of the title compound as a white solid: mp 104-105° C.; EIMS (70eV) m/z (relative intensity) 277 (20, M⁺).

Example 41 4-(4-Benzylpiperazin-1-yl)benzoic Acid

4-(4-Benzylpiperazin-1-yl) benzonitrile (4.0 g, 15 mmol) was dissolvedin glacial acetic acid (40 mL), 6 M hydrochloric acid (50 mL) was addedand the reaction mixture was stirred at 100° C. for 17 h. The solventwas evaporated, the residue was suspended in water (10 mL) and the pHwas adjusted to 3 by addition of 2 M sodium hydroxide (35 ml). Theslurry was stirred at 50° C. for 2 h, cooled and the precipitate wasfiltered and dried in vacuo to give 4.1 g of a crude product. The solidwas partitioned between methylene chloride (40 mL) and water (220 mL)with 2 M sodium hydroxide (8 mL). The aqueous phase was washed withmethylene chloride (40 mL) and the pH was adjusted to 5 with 2 Mhydrochloric acid. The aqueous phase was cooled, the precipitate wasfiltered and dried in vacuo to give 1.6 g (38% yield) of the titlecompound: mp 226° C. (dec); EIMS (70 eV) m/z (relative intensity) 296(44, M⁺).

Example 42 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide

A suspension of 4-(4-benzylpiperazin-1-yl)benzoic acid (1.3 g, 4.2 mmol)and 1,1′-carbonyldiimidazole (740 mg, 4.2 mmol) in N,N-dimethylformamide(30 mL) was heated to 75° C. for 1.5 h. The reaction mixture was cooledto 50° C. and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran (1.0 g, 4.0 mmol) was added. The solution wasstirred at 50° C. for 20 h and the solvent was evaporated in vacuogiving 3.5 g of a crude product. Purification by chromatography on asilica gel column using chloroform/methanol/concentrated ammonia95:5:0.5 as the eluent gave 1.7 g (80% yield) 25 of the title compoundas a pale yellow solid: mp sinters >85° C.; TSPMS m/z (relativeintensity) 526 (100, M+1); [α]²² _(D) −130° (c 1.0, chloroform).

Example 43 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(piperazin-1-yl)benzamide

(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide (1.7g, 3.2 mmol) was dissolved in methanol (100 mL). Palladium (10%) onactivated carbon (510 mg) and ammonium formate (1.6 g, 26 mmol) wereadded and the reaction mixture was stirred at 50° C. for 19 h. Thecatalyst was filtered off and the solvent was evaporated in vacuo togive 1.3 g (92% yield) of the title compound as a pale yellow solid:mp >102° C. sinters; EIMS (70 eV) m/z (relative intensity) 435 (8, M⁺);[α]²² _(D) −102° (c 0.15, chloroform).

Example 44 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(4-acetylpiperazin-1-yl)benzamide

(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(piperazin-1-yl)benzamide (460 mg, 1.0mmol) was dissolved in N,N-dimethylformamide (5 mL) and acetyl chloride(82 μL, 1.2 mmol) was added. The solution was stirred at ambienttemperature for 1 h and the solvent was evaporated in vacuo. The residuewas partitioned between methylene chloride (80 mL) and 2 M NaOH (10 mL).The organic layer was washed with brine (5 irL) and dried (MgSO₄).Evaporation of the solvent in vacuo gave 660 mg of a crude product.Purification by column chromatography on silica using chloroform/ethanol(saturated with ammonia) 15:1 as the eluent afforded 330 mg (66% yield)of the title compound as a white solid: mp 88° C. (dec); EIMS (70 eV)m/z (relative intensity) 477 (3, M⁺), [α]²² _(D) −138° (c 1.05,chloroform).

Example 45 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl)-4-(morpholinocarbonyl)benzamide

4-(Morpholinocarbonyl)benzoic acid (100 mg, 0.43 mmol; described in: J.Med. Chem. 1994, 37(26), 4538-4554) and 1,1′-carbonyldiimidazole (76 mg,0.47 mmol) were dissolved in N,N-dimethylformamide (3 mL) and heated to75° C. for 3.5 h. Additional 1,1′-carbonyldiimidazole (36 mg, 0.22 mol)was added and the solution was stirred for 30 min.(S)-3-Amino-5-(4-methylpiperazin-1-yl)-3,4 dihydropyran-2H-1-benzopyran(100 mg, 0.40 mmol), dissolved in N,N-dimethylformamide (2 mL), wasadded and the reaction mixture was stirred for 18 h at 50° C. Thesolvent was evaporated and the residue was partitioned between ethylacetate (30 mL) and water (5 mL). The organic layer was washed withwater (5 mL) and brine (5 mL) and dried (MgSO₄). The solvent wasevaporated in vacuo giving 180 mg of a crude product. Purification bypreparative TLC twice using chloroform/methanol/concentrated ammonia95:5:0.5 and chloroform/ethanol (saturated with NH₃) 12:1 as the eluentsafforded 98 mg (53% yield) of the title compound as a white solid: mp222° C. (decomposes); EIMS (70 eV) m/z (relative intensity) 464 (68,M⁺); [α]²² _(D) −12° (c 0.44, chloroform).

Example 46(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-benzopyran-3-yl)-4-(N,N-dimethylaminocarbonyl)benzamide

To 4-(N,N-dimethylaminocarbonyl)benzoic acid (110 mg, 0.56 mmol;described in: U.S. Pat, No. 3,607,918, 1971) was dropwise added thionylchloride (500 μL, 6.9 mmol). The reaction mixture was stirred at ambienttemperature for 1 min and then concentrated in vacuo. The excess ofthionyl chloride was co-evaporated with toluene in vacuo. The crude acidchloride was dissolved in methylene chloride (8 mL) and dropwise addedto a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran (130 mg, 0.53 mmol) and triethylamine (110 μL,0.80 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixturewas stirred at 0° C. for 30 min and at room temperature for anadditional 30 min. The solvent was evaporated in vacuo giving 300 mg ofa crude product. Purification by preparative TLC on silica usingchloroform/ethanol (saturated with ammonia) 10:1 as the eluent afforded120 mg (54% yield) of the title compound as a white solid: mp 219° C.(dec); EIMS (70 eV) m/z (relative intensity) 422 (47, M⁺); [α]²² _(D)−12° (c 0.42, chloroform).

Example 47 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-[4-(2-benzyloxyethyl)-piperazin-1-yl]benzamide

(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-(piperazin-1-yl)benzamide (500 mg, 1.2mmol) was dissolved in N,N-dimethylformamide (5 mL) and potassiumcarbonate (170 mg, 1.3 mmol) was added. To the mixture was added asolution of 2-benzyloxyethyl mesylate (290 mg, 1.3 mmol) (described in:Beard, C; Edwards, J; Fried, J. U.S. Pat. No. 3,929,824, 1972) inN,N-dimethylformamide (5 mL). The reaction mixture was stirred at 40° C.for 24 h. The solvent was evaporated in vacuo giving 950 mg of a crudeproduct. Purification by column chromatography on silica gel usingchloroform/methanol/concentrated ammonia 95:5:0.5 as the eluent afforded154 mg (24% yield) of the title compound as an oil: EIMS (70 eV) m/z(relative intensity) 569 (3, M⁺).

Example 48 (S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-[4-(2-hydroxyethyl)-piperazin-1-yl]benzamide

(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4dihydro-2H-1-benzopyran-3-yl]-4-[4-(2-benzyloxyethyl)-piperazin-1-yl]benzamide(150 mg, 0.27 mmol) was dissolved in acetic acid (10 mL) and palladium(10%) on carbon (12 mg) was added. Hydrogenation at room temperature andat atmospheric pressure for 14 h followed by filtration and evaporationof the solvent in vacuo gave 180 mg of a crude product. The residue waspartitioned between methylene chloride (60 mL) and 2 M NH₃ (5 mL) andwashed with brine (5 mL). Drying (MgSO₄) the solution and evaporation ofthe solvent in vacuo gave 120 mg of crude material. Purification bypreparative TLC on silica using chloroform/methanol/concentrated ammonia95:5:0.5 as the eluent afforded 37 mg (29% yield) of the title compoundas a white solid: mp 211-212° C.; EIMS (70 eV) m/z (relative intensity)479 (8, M⁺); [α]²² _(D) −26° (c 0.26, chloroform).

Pharmacology

Electrical Field Stimulation of [³H]-5-HT Release from OccipitalCortices of Guinea Pigs

[³H]-5-HT is released by electrical field stimulation from slices ofoccipital cortices of guinea pigs which have been pre-incubated with[³H]-5-HT. This release is similar to that caused by nerve stimulation,i.e. exocytotic release from serotoninergic nerve terminals, dependingon the presence of Ca²⁺ in the incubation medium. The 5-HT release isregulated at the level of the nerve terminals by autoreceptors, in theguinea pigs (like in humans) belonging to the h5-HT1B receptor subtype.Thus, agonists of h5-HT_(1B) receptors reduce the amount of [³H]-5-HTreleased by electrical field stimulation whereas the release isincreased by antagonists of this receptor type. Testing compounds withthis method is accordingly a convenient screening technique fordetermining the potency and functional effect of new h5-HT_(1B) receptoragonists and antagonists.

Methods and Materials

Buffer composition (mM) NaHCO₃ (25), NaH₂PO₄.H₂O (1.2), NaCl (117), KCl(6), MgSO₄×7H₂O (1.2), CaCl₂ (1.3), EDTA Na₂ (0.03). The buffer isgassed for at least 30 min before use. The pH of the buffer is about 7.2in the room temperature but it rises to about 7.4 at 37° C.

Preparation of Occipital Cortical Slices

Guinea pigs (200-250 g) were decapitated and the whole brains wereremoved. The occipital cortices were dissected and cut to slices 0.4×4mm with a McIlwain chopper machine. The white part of the tissue shouldbe removed carefully with a tweezer before slicing. The slices wereincubated in 5 ml buffer in the presence of 5 mM pargyline chloride.After incubation with 0.1 mM [³H]-5-HT for another 30 min the sliceswere transferred to a test tube and washed three times with same volumebuffer. The slices were transferred to the superfusion chambers with aplastic pipette and were washed for 40 min with the buffer in thepresence of the uptake inhibitor citalopram at 2.5 μM with a flow rateof 0.5 ml/min.

Electrical Stimulation of 5-HT Release

The superfused buffer was collected in 2 mL/fraction. The slices werestimulated by electricity with a train of pulses of frequency 3 Hz,duration 2 ms and current 30 mA for 3 min at the 4th and 13th fractions.The tested drugs were added from the 8th fraction to the end ofexperiment.

Results

A first electrical (or K⁺) stimulation results in a standard amount of[³H]-5-HT released (S₁). Between the first and the second stimulationthe h5-HT_(1B) antagonist is added to the media, which results in adose-dependent increase of the release (S₂) after the secondstimulation. See FIG. 1.

The S₂/S₁ ratio, which is the percent of released [³H]-5-HT at thesecond stimulation (S₂) divided by that of the first stimulation (S₁),was used to estimate drug effects on transmitter release.

1. A compound of formula (I)

wherein X is N; Y is NR₂CH₂, CH₂NR₂, NR₂CO, CONR₂, NR₂SO₂ or NR₂CONR₂wherein R₂ is H or C₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl or C₃-C₆cycloalkyl; R₃ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or (CH₂)_(n)-aryl,wherein aryl is a heteroaromatic ring containing one or two heteroatomsselected from N, O and S and which may be mono- or di-substituted withR₄ and/or R₅; wherein R₄ is selected from the group consisting of a) H,b) C₁-C₆ alkyl, c) C₃-C₆ cycloalkyl, d) halogen, e) CN, f) CF₃, g) OH,h) C₁-C₆ alkoxy, i) NR₆R₇, j) OCF₃, k) SO₃CH₃, l) SO₃CF₃, m) SO₂NR₆R₇,n) phenyl, o) phenyl-C₁-C₆ alkyl, p) phenoxy, q) C₁-C₆ alkylphenyl, r)an optionally substituted heterocyclic ring containing one or twoheteroatoms selected from N, O, S, SO and SO₂ wherein the substituent(s)is(are) selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl-C₁-C₆ alkyl,(CH₂)_(m) OR₉ wherein m is 2-6 and R₉ is H, C₁-C₆ alkyl, C₃-C₆cycloalkyl or phenyl-C₁-C₆ alkyl, and COR₈, s) an optionally substitutedheteroaromatic ring containing one or two heteroatoms selected from N, Oand S wherein the ring substituent(s) is(are) selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl and phenyl-C₁-C₆ alkyl, andt) COR₈; wherein R₆ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R₇ is H,C₁-C₆ alkyl or C₃-C₆ cycloalkyl; and R₈ is C₁-C₆ alkyl, C₃-C₆cycloalkyl, CF₃, NR₆R₇ or phenyl; R₅ is H, OH, TF₃, OCF₃, halogen, C₁-C₆alkyl or C₁-C₆ alkoxy; and n is 0-4; wherein the compound is an(R)-enantiomer, an (S)-enantiomer, or a racemate in the form of a freebase or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound according to claim 1 wherein Y is NR₂CO or CONR₂.
 3. Thecompound according to claim 1 wherein R₁ is H or C₁-C₆ alkyl.
 4. Thecompound according to claim 1 wherein R₃ is (CH₂)_(n)-aryl.
 5. Thecompound according to claim 1 wherein R₃ is (CH₂)_(n)-aryl which issubstituted with R₄, which is an optionally substituted heterocyclic orheteroaromatic ring containing one or two heteroatoms selected from N, Oand S, or COR₈.
 6. The compound according to claim 4 or 5 wherein n is0.
 7. The compound according to claim 5 wherein R₈ is NR₆R₇.
 8. Thecompound according to claim 2 wherein Y is NR₂CO.
 9. The compoundaccording to claim 8 wherein R₄ is morpholino or COR₈.
 10. Apharmaceutical formulation comprising as active ingredient atherapeutically effective amount of the compound of claim 1 as anenantiomer or racemate, in the form of a base or a pharmaceuticallyacceptable salt or solvate thereof optionally in association withdiluents, excipients or inert carriers.
 11. A method for the treatmentof 5-hydroxytryptamine-mediated disorders comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound defined in claim
 1. 12. A method for the treatment of5-hydroxytryptamine-mediated disorders comprising administering to apatient in need of such treatment a therapeutically effective amount ofthe pharmaceutical formulation of claim
 10. 13. A method for thetreatment of 5-hydroxytryptamine-mediated disorders in the centralnervous system which require treatment with an h5-HT_(1B) antagonist,which comprises administering to a patient in need of such treatment atherapeutically effective amount of a compound defined in claim
 1. 14. Aprocess for the preparation of the compound of formula I according toclaim 1 comprising: A(i) acylation, in the case wherein R₁ is C₁-C₆alkyl or C₃-C₆ cycloalkyl, Y is NR₂CO, R₂ is hydrogen and X and R₃ areas defined in claim 1, of a compound of formula A,

with an activated carboxylic acid R₃—COLg₁ wherein Lg₁ is a leavinggroup; or with a carboxylic acid R₃—COOH and an activating reagent;A(ii) acylation, in the case wherein R₁ is hydrogen, Y is NR₂CO, R₂ ishydrogen, R_(c) is a protecting group and X and R₃ are as defined inclaim 1, of a compound of formula B,

with an activated carboxylic acid R₃—COLg₁ wherein Lg₁ is a leavinggroup; or with a carboxylic acid R₃—COOH and an activating reagent, andremoving the protecting group R_(c); A(iii) debenzylation, in the casewherein R₁ is C₁-C₆ alkyl or C₃-C₆ cycoalkyl, X and R₂ are as defined inclaim 1 and R₉ below is C₁-C₆ alkyl, C₃-C₆ cycoalkyl, (CH₂)_(m)OHwherein m is 2-6 or COR₈, of a compound of formula Ia, followed by a)hydrogenation, b) alkylation, c) alkylation and removal of a protectinggroup or, d) acylation;

B(i) reacting, in the case wherein R₁ is C₁-C₆ alkyl or C₃-C₆ cycoalkyl,Y is CONR₂, and X, R₂ and R₃ are as defined in claim 1, an activatedcarboxylic acid of a compound of formula C;

with an aniline or an amine HNR₂R₃; or B(ii) reacting in the casewherein R₁ is hydrogen, Y is NR₂CO, R_(c) is a protecting group and X,R₂ and R₃ are as defined in claim 1, an activated carboxylic acid of acompound formula D,

with an aniline or an amine HNR₂R₃, and removing the protecting groupR_(c); or C reacting, in the case wherein R₁ is C₁-C₆ alkyl or C₃-C₆cycoalkyl, Y is NR₂CONR₂, R₂ is hydrogen and X and R₃ are as defined inclaim 1, a compound of formula A,

with a suitable azide in the presence of a carboxylic acid, R₃COOH.